Shedding Syndecan Creates Glypican Dependence

Heparan sulfate proteoglycans (HSPGs) serve as cofactors for many growth factors. HSPGs can be transmembrane proteins or can be anchored to the cell surface with a glycosylphosphatidylinositol (GPI) moiety. Many cells, including cancer cells, have both types of HSPGs on their surfaces. Ding et al. show that the pancreatic carcinoma cell line PANC-1 becomes dependent on the GPI-anchored HSPG glypican-1 for mitogenic response to fibroblast growth factor 2 (FGF2) after initial stimulation with FGF2. Treatment of the cells with phosphatidylinositol phospholipase C (PIPLC) to selectively cleave GPI-anchored proteins decreased the response of PANC-1 cells and the breast carcinoma cell line MDA-MB-468 to FGF2. Cells expressing a transmembrane variant of glypican-1 did not show this loss of responsiveness after PIPLC treatment. PIPLC and trypsin treatment of unstimulated cells showed that both GPI-anchored and transmembrane HSPGs were present on the surface of PANC-1 cells, and stimulation with FGF2 caused the selective loss of the transmembrane HSPG. The dependence on glypican-1 for mitogenic response was eliminated if the cells were transfected with a mutant form of the HSPG syndecan-1 that was not subject to cleavage by growth factor-regulated matrix metalloproteinase (MMP). Pharmacological inhibition of MMP also prevented PIPLC from decreasing FGF2 responsiveness in the PANC-1 and MDA-MB-468 cells. MMP7 appeared to be the enzyme responsible for syndecan-1 shedding in response to FGF2 stimulation, because active MMP7, which binds to heparan sulfate, was released in response to FGF2 (presumably due to cleavage and shedding of one of its binding partners, syndecan-1), and a function-blocking antibody prevented PIPLC from decreasing the response to FGF2. These results indicate that, in tumor cells, the GPI-anchored glypican-1 may serve as the growth factor cofactor for mitogenic signaling and the transmembrane syndecan-1 is released from the cell surface to serve a different, yet to be determined, function.